Project Summary Retinopathy of prematurity (ROP) is a leading cause of vision loss in children and is currently treated by laser therapy or cryotherapy. However, both treatments destroy the peripheral vision to save the central vision with limited efficacy and do not address the underlying cause of pathological retinal neovascularization. There is no approved drug therapy for ROP. Vascular endothelial growth factor (VEGF) is critical to vascular and retinal development in embryos, and anti-VEGF therapy interferes with vasculogenesis and retinogenesis in premature infants, leading to adverse effects. As a result, VEGF inhibitors are not approved for ROP therapy. To address this urgent unmet clinical need, we recently discovered secretogranin III (Scg3) as a highly disease-restricted pro-angiogenic factor that preferentially binds to and stimulates angiogenesis of diseased but not normal vessels. This is in contrast to VEGF which indiscriminately binds to and induces angiogenesis of both diseased and normal vessels. Among thousands of quantified endothelial ligands, Scg3 had the highest binding activity ratio to diseased vs. control vasculature and lowest binding to normal retina. Therefore, Scg3 represents the first highly disease-selective angiogenic factor. We developed Scg3-neutralizing monoclonal antibodies (mAb) and demonstrated high efficacy and safety to alleviate ROP in animal models. The safety of anti-Scg3 therapy is also supported by the normal development of Scg3 knockout mice, whereas VEGF knockout mice are embryonic lethal with severely defective vasculogenesis. We hypothesize that Scg3-neutralizing antibody represent a new class of selective angiogenesis blockers to alleviate ROP with high efficacy and minimal side effects on the developing retina. In Aim 1, we will characterize the pharmacodynamic characteristics of humanized anti-Scg3 antibody (hAb). In Aim 2, we will delineate the unique mechanisms of action of the Scg3 hAb as a selective angiogenesis blocker. In Aim 3, we will investigate preclinical safety and pharmacokinetics of anti-Scg3 hAb. To our knowledge, anti-Scg3 antibody is the first selective angiogenesis blocker described to date. Therefore, this project is to develop not just another novel anti-angiogenic drug, but a founding member of a new class of selective angiogenesis blockers for targeted therapy. The outcomes of this project will facilitate the discovery and development of other selective angiogenic factors and their inhibitors. Successful implementation of this project will lead to a first-in-human clinical trial for this new class of selective blockers. Anti-Scg3 antibody has the potential to become the first approved drug for ROP therapy to save the vision of thousands of ROP infants each year.